901-64 Heterogeneous Sympathetic Innervation in German Shepherd Dogs with Inherited Ventricular Arrhythmia and Sudden Death

An inbred colony of German Shepherd dogs with spontaneous ventricular arrhythmias and sudden death has recently been identified. The median age of onset of the arrhythmia (4.5 months), the tendency for sudden death to occur during REM sleep, during/following exercise, and the absence of structural heart disease suggest a developmental abnormality of the autonomic innervation to the heart. To further evaluate this possibility, we studied 7 dogs from this colony, mean age 5.2 months. Three of seven were severely affected (frequent VT on holter). two were mildly affected, and two had no arrhythmias by holter analysis. We imaged the distribution of functional myocardial sympathetic innervation and perfusion using I-123 metaiodobenzylguanidine (MIBG) and thallium-201 respectively. Sympathetic nerve distribution was evaluated morphologically by immunocytochemical localization of tyrosine hydroxylase. Six mCi of I-123 MIBG was injected IV followed three hours later by 2 mCi of thallium-201. The hearts were excised, sliced transversely, and imaged directly for MIBG and thallium. Color functional maps were derived to display the distribution of innervation (MIBG) and perfusion (thallium-2011 simultaneously. Following imaging, the slices were fixed in formaldehyde then stored at 4°C in 30% sucrose/phosphate buffer until processing for immunohistochemistry. All of the hearts showed homogeneous thallium perfusion, however there was evidence of a regional decrease in MIBG uptake ranging from 10% to 45% of the left ventricle, consistent with regional denervation. The defects were generally localized to the anterior and septal territories. Immunocytochemial studies on sections from regions with decreased MIBG uptake showed a striking paucity of nerves compared to regions with normal MIBG uptake, confirming denelVation. While all of the hearts showed denelVation, 2/3 with severe arrhythmia showed either extensive denervation or a steep gradient in MIBG uptake, while 1/4 of the mildly affected or dogs without arrhythmias showed extensive denervation. We conclude that there is abnormal heterogeneous sympathetic innervation in this population of dogs with spontaneous naturally occurring ventricular arrhythmias and increased incidence of sudden cardiac death. This heterogeneity of innervation may playa role in the etiology of ventricular arrhythmia, particularly during states of increased sympathetic tone.